Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy

Clin Pharmacokinet. 2017 Nov;56(11):1403-1413. doi: 10.1007/s40262-017-0530-8.


Objectives: To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen.

Methods: Structural time-to-event models for dropouts (not because of a lack of efficacy) and seizures were developed using data from 883 adult patients newly diagnosed with epilepsy and experiencing focal or generalized tonic-clonic seizures, participating in a trial (SP0993; ClinicalTrials.gov identifier: NCT01243177) comparing the efficacy of lacosamide and carbamazepine controlled-release monotherapy. Lacosamide dropout and seizure models were used for simulating the effect of changing the initial target dose on seizure freedom.

Results: Repeated time-to-seizure data were described by a Weibull distribution with parameters estimated separately for the first and subsequent seizures. Daily area under the plasma concentration-time curve was related linearly to the log-hazard. Disease severity, expressed as the number of seizures during the 3 months before the trial (baseline), was a strong predictor of seizure probability: patients with 7-50 seizures at baseline had a 2.6-fold (90% confidence interval 2.01-3.31) higher risk of seizures compared with the reference two to six seizures. Simulations suggested that a 400-mg/day, rather than a 200-mg/day initial target dose for patients with seven or more seizures at baseline could potentially result in an additional 8% of seizure-free patients for 6 months at the last evaluated dose level. Patients receiving lacosamide had a slightly lower dropout risk compared with those receiving carbamazepine.

Conclusion: Baseline disease severity was the most important predictor of seizure probability. Simulations suggest that an initial target dose >200 mg/day could potentially benefit patients with greater disease severity.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Acetamides / blood
  • Acetamides / pharmacokinetics
  • Acetamides / therapeutic use*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anticonvulsants / blood
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / therapeutic use
  • Computer Simulation
  • Double-Blind Method
  • Epilepsy / blood
  • Epilepsy / drug therapy*
  • Female
  • Humans
  • Lacosamide
  • Male
  • Middle Aged
  • Models, Biological
  • Patient Dropouts
  • Seizures / drug therapy*
  • Severity of Illness Index
  • Time Factors
  • Young Adult


  • Acetamides
  • Anticonvulsants
  • Lacosamide

Associated data

  • ClinicalTrials.gov/NCT01243177